Alcoholism is a tremendous health and financial burden on our society. A growing literature indicates that a series of interconnected brain regions referred to as the extended amygdala plays a key role in alcohol-related behaviors. In isolated studies, we and others have identified adaptations that occur at synapses in these regions in response to acute and chronic ethanol exposure. Here, we propose experiments to in parallel examine key points in this circuitry for their responses to a common alcohol treatment regimen, to better determine the concerted effects of ethanol and ethanol withdrawal. Moreover, we will assess molecular mechanisms involved in these actions through the use of a new conditional knockout mouse for the NMDA receptor subunit NR2B combined with a viral-directed knockout strategy. In total, the proposed work will begin to define specific mechanisms likely to play key roles in pathological adaptations and behaviors associated with chronic alcohol intake, thus providing new potential opportunities for therapeutic development.